Hydroxamic acid derivatives of 7-[(2-amino-4-thiazolyl)-oximino] cephalosporins

ABSTRACT

A compound of the formula ##STR1## wherein R is hydrogen, alkali metal, ##STR2## or ##STR3## R 1  is hydrogen or methyl; R 2  is hydrogen or methyl; 
     R 3  is hydrogen, lower alkyl or lower alkylphenyl; 
     R 4  is hydrogen, --OCONH 2 , ##STR4## R 7  is hydrogen or lower alkyl; R 8  is hydrogen or --CONH 2  ; 
     R 9  is hydrogen, lower alkyl, ##STR5##  or --(CH 2 ) p  --N--(lower alkyl) 2  ; R 10  is hydrogen or lower alkyl; 
     R 11  is hydrogen, sodium or potassium; 
     n is 1, 2, 3 or 4; 
     m is 0, 1 or 2; 
     p is 1, 2, 3 or 4.

BACKGROUND OF THE INVENTION

Hoechst in German Offenlegungsschrift No. 2,714,880 disclose antibacterially active cephalosporins including those of the formula ##STR6## wherein R₃ is hydrogen; R₄ is hydrogen or alkoxy; A is various 3-position substituents; and R₂ is defined as alkyl of 1 to 4 carbons, for example methyl, having one or more substituents.

Hoechst in German Offenlegungsschrift No. 2,716,677 disclose antibacterially active cephalosporins including those of the formula ##STR7## wherein X is an α- or β- --SO, or an SO₂ group; R₄ is hydrogen or alkoxy; A is various 3-position substituents; and R₂ is defined as an alkyl of 1 to 4 carbons, for example methyl, having one or more substituents.

Takaya et al. U.S. Pat. No. 4,166,115 disclose 3,7-disubstituted-3-cephem-4-carboxylic acid compounds of the general formula: ##STR8## in which R₁ may be a group of the formula: ##STR9## wherein R⁷ is amino or protected amino; R₂ is an aliphatic hydrocarbon group which may have suitable substituents such as various heterocyclic groups, R₃ is carboxy or protected carboxy, and R₄ is methyl, acyloxymethyl, hydroxymethyl, formyl or a substituted heterocyclicthiomethyl group.

Heynes et al. in U.S. Pat. No. 4,152,432 discloses compounds of the formula: ##STR10## wherein R¹ is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl and alkynyl of 2 to 4 carbon atoms and groups easily removable by acid hydrolysis or hydrogenolysis.

Ochiai et al. in U.S. Pat. No. 4,098,888 discloses compounds of the formula: ##STR11## wherein R₂ represents amino or hydroxyl group or a group convertible into these groups.

SUMMARY OF THE INVENTION

This invention is directed to cephalosporins of the formula: ##STR12## wherein R is hydrogen, alkali metal, ##STR13## alkyl, Si(CH₃)₃, p-methoxybenzyl, diphenylmethyl, benzyl, trichloroethyl, ##STR14## or lower alkyl; R₁ and R₂ are independently selected from hydrogen and methyl;

R₃ is hydrogen, alkylphenyl or alkyl;

R₄ is hydrogen, --OCONH₂, ##STR15## R₇ is hydrogen or lower alkyl; R₈ is hydrogen or --CONH₂ ;

R₉ is hydrogen, lower alkyl, ##STR16## or --(CH₂)_(p) --N--(lower alkyl)₂ ; R₁₀ is hydrogen or lower alkyl;

R₁₁ is hydrogen, sodium or potassium;

n is 1, 2, 3 or 4;

m is 0, 1 or 2;

p is 1, 2, 3 or 4;

When R₄ is pyridinium or carbamoyl substituted pyridinium, the compounds can be structurally represented as having the formula: ##STR17## wherein R₈ is hydrogen or carbamoyl.

DETAILED DESCRIPTION OF THE INVENTION

The lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing 1 to 4 carbons, e.g., methyl, ethyl, i-propyl, t-butyl, etc.

The compounds of formula I and their intermediates that are described below that have the 2-amino 4-thiazolyl group as part of their structure are, of course, tautomeric and can also be structurally represented as containing a 2-imino group. Thus, the compounds of formula I can be represented as: ##STR18##

The intermediates and final products are being structurally represented and named throughout this specification as 2-amino-4-thiazoles though both forms are within the scope of the invention.

The compounds of formula I and the intermediates described below having the oximino substituent ##STR19## can be obtained as the syn or anti isomer or as a mixture of isomers. All of these isomeric forms are within the scope of this invention. However, in general, it is preferred to obtain the final products in the syn form since that isomeric form has the greatest activity.

The symbol ##STR20## is being used to represent sulfide alone or bonded to either one or two oxygens. When the sulfide is bonded to only one oxygen the sulfoxides of formula I and in the various intermediates described below can be in either the α- or β-configuration. When the sulfoxide is only in the β-configuration it will be represented as ##STR21## and when it is only in the α-configuration it will be represented as ##STR22##

The cephalosporins of formula I can be prepared by various methods. For example, the compounds of formula I wherein R₄ is --OCONH₂, ##STR23## and wherein R₉ and R₁₀ are as defined above and can be obtained by acylating an ester of the formula: ##STR24## wherein R₄, and m are as defined above and R is an ester protecting group such as benzyl, diphenylmethyl, t-butyl, p-methoxybenzyl or trichloroethyl, with a compound of the formula: ##STR25## wherein R₁, R₂, R₃, and n are as defined above, to yield an intermediate of the formula ##STR26##

The acylation reaction is carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide.

The intermediate of formula V is then treated to remove the ester protecting group and yield the compounds of formula I in the acid form. Preferably, in the above reactions, R is diphenylmethyl and the intermediate of formula V is treated with trifluoroacetic acid to remove the diphenylmethyl group.

The compounds of formula IV are obtained by reacting 2-amino-4-thiazole glyoxylic acid of the formula ##STR27## with a compound of the formula ##STR28##

The compound of formula VII can be prepared by treating N-hydroxyphthalimide sodium salt with a compound of the formula ##STR29## to yield the compound of the formula ##STR30##

Treatment of IX with hydrochloric acid yields the reactant of formula VII.

The 7-amino cephalosporanic acid ester α- and β-sulfoxides of formula III (m is one) are prepared by converting the 7-amino cephalosporanic acid starting material (m is zero) to the Schiff base ester of the formula ##STR31## which is then oxidized with a percarboxylic acid such as m-chloroperbenzoic acid to yield a mixture of α- and β-sulfoxide Schiff base cephalosporin esters. The Schiff base sidechain is cleaved by treatment with toluenesulfonic acid and the α- and β-sulfoxide 7-amino cephalosporanic acid esters are separated chromatographically. Further oxidation of the α-sulfoxide yields the corresponding sulfone (m is two) of formula III.

The compounds of formula Ia can be prepared by reacting a compound of formula I wherein R is hydrogen and R₄ is ##STR32## with pyridine or carbamoyl substituted pyridine in a polar solvent such as water and in the presence of a catalyst such as an alkali metal thiocyanate according to the procedures taught in U.S. Pat. No. 3,792,047 and German Offenlegungsschrift No. 2,234,280.

Also, the compounds of formula I wherein R₄ is heterothio ##STR33## can be prepared by reacting the compound of formula I wherein R is hydrogen and R₄ is ##STR34## with a mercaptan of the formula

    hetero-S-H

or an alkali metal (preferably sodium) mercaptan salt of the formula

    hetero-S-alkali metal.

Such methods of introducing a heterothio group in the 3-position are disclosed in various U.S. Pat. Nos. including 3,955,213, 4,066,762, etc.

The β-sulfoxide compounds of formula I (m is one) can also be prepared by the direct oxidation of the corresponding sulfide compound (m is zero). Suitable oxidizing agents are percarboxylic acids such as m-chloroperbenzoic acid, peracetic acid, etc., and this reaction can be performed at from about 0° C. to about 25° C.

Also, the sulfone compounds of formula I (m is two) can be prepared by the direct oxidation of the corresponding α-sulfoxide compound (m is one). Again percarboxylic acids such as m-chloroperbenzoic acid and peracetic acid are the preferred oxidizing agents.

The compounds of formula I wherein R is sodium or potassium are prepared by reacting the corresponding compound of formula I wherein R is hydrogen with the appropriate salt forming ion.

The compounds of formula I wherein R is ##STR35## can be obtained by treating the corresponding free acid of formula I with a compound of the formula ##STR36## wherein halo is chlorine or bromine in an inert solvent such as dimethylformamide at or below ambient temperature.

Similarly, the compounds of formula I wherein R is ##STR37## are prepared by treating free acid compound of formula I with a compound of the formula ##STR38## wherein L is hydroxy or Br as taught in U.S. Pat. Nos. 3,860,579, 3,951,954, and 4,072,677.

Preferred compounds of this invention are those of formula I wherein the oximino group is in the syn configuration;

n is one or two

m is zero or one provided that when m is one the sulfoxide is in the β-configuration;

R is hydrogen, sodium or potassium;

R₁, R₂, R₃ are independently selected from hydrogen and methyl; ##STR39## R₇ is hydrogen; R₈ is hydrogen or ##STR40## R₉ is hydrogen, methyl, ##STR41## or --(CH₂)_(p) --N(CH₃)₂ ; R₁₁ is hydrogen, sodium or potassium and p is 1 or 2.

Most preferred are the above compounds wherein R₄ is ##STR42##

The compounds of formula I wherein R is hydrogen, sodium, potassium ##STR43## are useful antibacterial agents possessing activity against various gram negative organisms including Klebsiella, Proteus, and Enterobacter species. These compounds are also active against strains of Escherichia coli, Citrobacter freundii, Salmonella typhimurium, etc. They may be used as antibacterial agents to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to other gram-negative antibacterial agents. For example, a compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 100 mg./kg., daily in parenteral form, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg., kg. in mice.

Up to about 600 mg. of an acid compound of formula I or a physiologically acceptable salt or ester thereof may be incorporated in an injectable form prepared according to conventional pharmaceutical practice.

Illustrative process details are in the examples for the various reactions. All temperatures are on the centigrade scale.

EXAMPLE 1 [6R-[6α,7β(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-oxo-2-[(phenylmethoxy)amino]ethoxy]imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt (a) [(1.3-dihydro-1.3-dioxo-2H-isoindole-2-yl)oxy]-N-(phenylmethoxy) acetamide

5 g of bromoacetyl hydroxamic acid, benzylester is added to a mixture of N-hydroxyphthalimide, 50 ml dimethylformamide and potassium carbonate with stirring. The temperature is maintained for 1.5 hours at 20° C. The solution is poured onto 500 g ice, acidified with concentrated hydrochloric acid and the precipitated compound is filtered off to yield 3.6 g of [(1.3-dihydro-1.3-dioxo-2H-isoindole-2-yl)oxy]-N-(phenylmethoxy) acetamide having a melting point of 118° C. to 120° C.

(b) 2-(Aminooxy)-N-(phenylmethoxy)acetamide, hydrochloride

5.0 g of [(1.3-dihydro-1,3-dioxo-2H-isoindole-2-yl)oxy]-N-(phenylmethoxy) acetamide is suspended in 100 ml anhydrous methanol. While stirring and maintaining the temperature at 0° C., 0.54 g hydrazine in 10 ml. methanol is added. Stirring is continued at 0° C. for 12 hours. After this time an equivalent amount of hydrochloric acid in methanol is added, the insoluble precipitate is filtered off and the mother liquor evaporated in vacuo. The residue is dissolved in a small amount of methanol, filtered and evaporated. The only residue is now treated with 100 ml of diethyl ether. 3.4 g of 2-(Aminooxy)-N-(phenylmethoxy)acetamide, hydrochloride having a melting point of 173° C. to 175° C. is filtered off.

(c) 2-Amino-α-[[2-oxo-2-[(phenylmethoxy)amino]-ethoxy]-imino]-4-thiazole-acetic acid

2.7 g of 2-(Aminooxy)-N-(phenylmethoxy)acetamide, hydrochloride made as in Example 1(b) and 2.3 g of 2-amino-thiazolyl-4-glyoxylic acid are stirred in 50 ml water at room temperature. The pH is adjusted to 6.5 with potassium carbonate and maintained for 12 hours between 6.5 and 7.0. After this time the solution is evaporated to about 10 ml and then acidified with concentrated hydrochloric acid to pH 1.5. 3.8 g of 2-amino-α-[[2-oxo-2-[(phenylmethoxy)amino]-ethoxy]imino]-4-thiazole-acetic acid precipitated having a melting point of 170° C. to 172° C. is filtered off.

(d) [6R-[6α,7β(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-oxo-2-[(phenylmethoxy)-amino]ethoxy]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester

1.0 g of 2-amino-α-[[2-oxo-2-[(phenylmethoxy) amino]ethoxy]imino-4-thiazole-acetic acid and 1.25 g 7-ACA diphenylmethyl ester are dissolved in 50 ml dry dimethylformamide and 100 ml acetonitrile. 0.40 g hydroxybenzotriazole is added and the solution is cooled to 0° C. 710 mg dicyclohexylcarbodiimide in 10 ml acetonitrile is added with stirring. Stirring is continued for 12 hours at 0° C. The precipitated urea is filtered off and the mother liquor evaporated in vacuo. The remaining residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and aqueous sodium chloride solution, dried over sodium sulfate and evaporated until a volume of about 10 ml is reached. This solution is poured with stirring into 100 ml diethyl ether. The precipitated [6R-[6α, 7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-oxo-2-[(phenylmethoxy)amino]-ethoxy]imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester is filtered off yielding 1.41 g melting point 103°-108° C.).

(e) [6R-[6α, 7β(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-oxo-2-[(phenylmethoxy)amino]ethoxy]imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt

1.32 g of [6R-[6α, 7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-oxo-2-[(phenylmethoxy)-amino]ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt made as in Example 1(d) is suspended at 0° C. with stirring in 3 ml of anisole. 6 ml trifluoroacetic acid is added and the temperature is maintained at 0° C. for 2 hours. After this time, the solution is poured into 100 ml of a 1:1 mixture of diethyl ether/petrol ether. The precipitate is filtered off to yield 0.95 g of [6R-[6α, 7β-(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)-[2-oxo-2-[(phenylmethoxy)amino]ethoxy]imino]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt, having a melting point of 95° C. to 100° C.

(f) [6R-[6α, 7β(Z)]]-3-[(Acetyloxy)methyl]-7-[[2-amino-4-thiazolyl)[2-oxo-2-[(phenylmethoxy)amino]ethoxy]imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt

While stirring 0.8 g of [6R-[6α, 7β(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-oxo-2-[(phenylmethoxy)amino]ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt is dissolved in 5 ml methanol. At 0° C. an equivalent amount of sodium ethyl hexanoate in butanol is added while stirring. After 10 min. 100 ml of dry diethyl ether is added and the precipitate is filtered off to yield 0.69 g of [6R-[6α, 7β(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-oxo-2-[(phenylmethoxy)amino]ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt having a melting point of 168° C. to 173° C.

EXAMPLE 2 [6R-[6α, 7β(Z)]]- 3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt. (a) [(1,3-Dihydro-1,3-dioxo-2H-isoindole-2yl)oxy]-N-(methoxy)acetamide

3.1 g potassium hydroxyphthalimide and 1.85 g chloroacetyl hydroxamic acid methyl ester are stirred together at 60° C. in 25 ml dry dimethylformamide for 1 hour. After this time the solution is poured on 100 g ice and the precipitate is filtered off to yield 1.5 g of [(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)oxy]-N-(methoxy)acetamide having a melting point of 179° C.

(b) (Aminooxy)-N-methoxy-acetamide-hydrochloride

2.5 g of [(1,3-Dihydro-1,3-dioxo-2H isoindole-2-yl)oxy]-N-(methoxy) acetamide made as in Example 2(a) is dissolved in 50 ml CH₃ OH at 0° C. with stirring. A solution of 0.35 g hydrazine in 10 ml methanol is added and stirring at 0° C. is continued for 12 hours. After this time an equivalent amount of hydrochloric acid in 5 ml CH₃ OH is added and the precipitate formed is filtered off. The mother liquor is evaporated to dryness and 2-(aminooxy)-N-(methoxy)acetamide, hydrochloride as a residual oil is formed and used in the next step without further purification.

(c) 2-Amino-α-[[2-oxo-2-(methoxy)amino]ethoxy]imino]-4-thiazole acetic acid

1.7 g of 2-Amino-thiazolyl-4-glyoxylic acid and 1.4 g 2-(aminooxy)-N-methoxy-acetamide-hydrochloride are suspended in 20 ml H₂ O and the pH is adjusted to 7 with potassium carbonate and maintained for 12 hours. After this time the pH is brought to 1.5 and 2-amino-α-[[2-oxo-2-(methoxy)amino]ethoxy]imino]-4-thiazole acetic acid is precipitated and filtered off with a yield of 1.8 g and a melting point of 154°-155° C.

(d) [6R-[6α, 7β(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester

900 mg 7ACA benzhydryl ester, 300 mg hydroxybenzotriazole and 550 mg of the compound of Example 2(c) are dissolved in 20 ml dimethylformamide (DMF) at 0° C. An equivalent amount of dicyclohexylcarbodiimide in 10 ml acetonitrile is added with stirring. The temperature is maintained at 0° C. for 12 hours. The acetonitrile is evaporated in vacuo and the DMF-solution poured into 0° C. water. The precipitate is filtered off and chromatographed via a SiO₂ column using ethyl acetate as eluent to yield 950 mg of [6R-[6α,7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester having a melting point of 115°-117° C.

(e) [6R-[6α,7β(Z)]]-3-[Acetyloxy methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt

70 mg of [6R-[6α,7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester is dissolved in 0.5 ml of anisole. At 0° C. 1 ml of trifluoroacetic acid is added and the temperature is maintained for 1 hour. The solution is then poured into 50 ml of diethyl ether and the precipitated acid collected by filtration to yield 35 mg of [6R-[6α,7β(Z)]]-3-[acetyloxy methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt.

(f) [6R-[6α,7β(Z)]]-3-[Acetyloxy methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethyoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt

20 mg of [6R-[6α,7β(Z)]]-3-[acetyloxy methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt is dissolved in 0.5 ml methanol and an equivalent amount of sodium ethyl hexanoate in butanol is added. After stirring for 10 minutes at 0° C., the solution is filtered to yield 12 mg of [6R-[6α,7β(Z)]]-3-[acetyloxy methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt having a melting point of 138°-142° C.

EXAMPLE 3 [6R-[6α,7β(Z)]]-3-[Acetyloxy methyl]-7-[[(2-amino-4-thiazolyl)[[2-(hydroxy amino)- 2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt

15 mg of [6R-[6α,7β(Z)]]-3-[Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-oxo-2-[(phenyl methoxy)amino]ethoxy]imino]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid of Example 1(e) are dissolved in 5 ml acetonitrile at room temperature with stirring. 100 mg of trimethyl-silyl iodide is added and stirring is continued for 12 hours. After this time 1 ml of CH₃ OH is added and the solution poured into 50 ml of ether. The precipitated [6R-[6α,7β(Z)]]-3-[acetyloxy methyl]-7-[[(2-amino-4-thiazolyl)[[2-(hydroxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is filtered off. The yield is 10 mg. This acid is dissolved in 0.5 ml acetone and an equivalent amount of sodium ethyl hexanoate in 0.5 ml butanol is added. After 5 minutes the solution is poured into 20 ml of ether. The sodium salt is filtered off yielding 8 mg of [6R-[6α,7β(Z)]]-3-[Acetyloxy methyl]-7-[[(2-amino-4-thiazolyl)]]2-(hydroxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt having a melting point of 159° C. to 161° C.

EXAMPLE 4 [5S-[5α,6β,7α(Z)]]-3-(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5 dioxide sodium salt (a) [5S-[5α,6β,7α]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., β-sulfoxide) and [5R-[5α,6α,7β]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., α-sulfoxide)

A slurry of 50 g of 7-aminocephalosporanic acid (7-ACA) in 1 liter of water is stirred magnetically while t-octyl amine is added dropwise, thereby maintaining the pH between 7 and 8. After one hour the undissolved solid is filtered (celite) and the filtrate is treated with a solution prepared by adjusting a mixture of 10 ml of t-octylamine and 20 ml of water to pH 8.0 with 6 N hydrochloric acid. The resulting solution is then treated with 10 ml of salicylaldehyde. After 2 minutes a solid forms and after 5 minutes an additional 10 ml of salicylaldehyde is added. The slurry is stirred for an additional 10 minutes, cooled to 0° C. for 4.5 hours and filtered. The filter cake is slurried twice with 300 ml of cold water and filtered. The wet cake is dried at 60° C. in vacuo over large amounts of P₂ O₅ to give 66 g of tan solid 7-salicyclaldiminocephalosporanic acid, t-octyl amine salt.

A slurry of 25.25 g (0.05 mole) of the above t-octyl amine salt (powdered with a mortar and pestle) in 250 ml of dry acetonitrile is treated with 9.5 g (0.05 mole) of p-toluenesulfonic acid monohydrate. After 10 minutes, a solution of 9.7 g (0.05 mole) of diphenyldiazomethane in 50 ml of acetonitrile is added over the course of 15 minutes. After one hour, the slurry is filtered, the solid is washed with acetonitrile, and the combined filtrate and washings are evaporated in vacuo. The resulting oil is chromatographed on a 300 g silica gel column eluted with methylene chloride. Fractions (500 ml) 2-3 contain 7.5 g of the desired diphenylmethyl ester product plus some higher R_(f) impurity (monitored by silica gel TLC with 3:1 chloroform-ethyl acetate development)-fractions 4-11 contain 12.3 g of pure 7-salicyclaldiminocephalosporanic acid, diphenylmethyl ester; NMR (CDCl₃) δ 1.97 (s, 3H, CH₃ CO); 3.23 and 3.60 (AB q, J=19 Hz, 2H, c-2); 4.67 and 5.01 (AB q, J=14 Hz, 2H, C-3'); 4.99 (d, J=5 Hz, 1H, c-6); 5.20 (broadened d, J=5 Hz, 1H, C-7); 6.62-7.60 (m, about 15H); 9.07 broad s, 1H, --CH═N--).

A solution of 12.3 g (0.023 mole) of the above diphenylmethyl ester product in 125 ml of methylene chloride is cooled to 0° and a solution of 4.6 g (0.023 mole) of 85% m-chloroperbenzoic acid in 70 ml of methylene chloride is added over the course of 15 minutes. After one hour, the slurry is washed with a mixture of 100 ml of 5% sodium bicarbonate and 50 ml of 6% sodium sulfite solution. The organic layer is dried and evaporated in vacuo. The resulting oil crystallizes from 70 ml of ethyl acetate giving 8.7 g of a mixture of α- and β-sulfoxides. A second crop of 1.5 g of a mixture of α- and β-sulfoxides is also obtained. The major (α-) isomer has a lower field acetate methyl (2.02 ppm) and C-2 quartet (3.57 and 4.10 ppm) when compared to those of the minor (β) isomer (1.97, 3.26 and 3.94 ppm, respectively).

A slurry of 10 g (0.018 mole) of the above 7-salicyclaldiminocephalosporanic acid, diphenylmethyl ester α- and β-sulfoxide mixture in 100 ml of ethyl acetate is treated with 3.42 g (0.018 mole) of p-toluenesulfonic acid monohydrate. After 5.5 hours, 300 ml of ether is added and the gummy solid is triturated, filtered, and washed twice with ether. The moist solid is dissolved in 200 ml of ethyl acetate and the solution is washed with 100 ml of 5% sodium bicarbonate solution, dried, and evaporated to give 8.0 g or residue. Chromatography on a 300 g silica gel column eluted with 3:1 chloroformethyl acetate gives (500 ml fractions)-fraction 3, 1.0 g of recovered 7-salicycldimino-cephalosporanic acid, diphenylmethyl ester; fractions 6-16, 4.5 g of [5R-[5α, 6α,7β]]-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., α-sulfoxide isomer):NMR (CDCl₃)δ 2.00 (CH₃ COO--); 3.43 and 4.06 ppm (AB q, C-2); fractions 22-30 (eluant is changed to ethyl acetate after fraction 16) 1.5 g of [5S-[5α,6β,7α]]-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., β-sulfoxide isomer):NMR (CDCl₃)δ 2.10 (CH₃ COO--); 2.97 and 3.54 ppm (AB q, C-2).

(b) [6R-[6α,7β]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester

[5R-[5α,6α,7β]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester from Example 4(a) is added to methylene chloride and cooled to 0°. An equimolar amount of m-chloroperbenzoic acid in methylene chloride is added. After the reaction is completed, the slurry is treated with 5% sodium bicarbonate and 5% sodium sulfite. The organic layer is dried and evaporated in vacuo Preparative thin layer chromatography of the residue yields [6R-[6α,7β]]-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[2.1.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester.

(c) [5S-[5α,6β,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester

Following the procedure of Example 2(d) but substituting [5S-[5α,6β,7α]]-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester for 7 ACA-diphenylmethyl ester then [5S-[5α,6β,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, 5,5 dioxide, diphenylmethyl ester is formed.

(d) [5S-(5α,6β,7α)]-3-(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5,5 dioxide trifluoroacetate salt

Following the procedure of Example 2(e) but substituting [5S-[5α,6β,7α(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5,5-dioxide diphenylmethyl ester for [6R-[6α,7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester then [5S-(5α,6β,7α]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5 dioxide trifluoroacetate salt is formed.

(e) [5S-[5α,6β,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[ 2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5 dioxide, sodium salt

Following the procedure of Example 2(f) but substituting [5S-(5α,6β,7α)]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5 dioxide trifluoroacetate salt for [6R-[6α,7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt to form [5S-[5α,6β,7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5 dioxide, sodium salt.

EXAMPLE 5 [5R-[5α,6α,7β]]-3-[(Acetyloxy)methyl]-7-[[ (2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt (i.e. α-sulfoxide) (a) [5R-[5α,6α,7β]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5-oxide, diphenylmethyl ester

Following the procedure of Example 2(d) but substituting [5R-[5α,6α,7β]]-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e. α-sulfoxide) made as in Example 4(a) for 7 ACA-diphenylmethyl ester, then [5R-[5α,6α,7β]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester is formed.

(b) [5R-[5α,6α,7β]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate

Following the procedure of Example 2(e) but substituting [5R-[5α,6α,7β]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl]-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5-oxide, diphenylmethyl ester in place of [6R-[6α,7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester then [5R-[5α,6α,7β]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate is formed.

(c) 5R-[5α,6α,7β]]-3-[[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[ [2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, 5-oxide, (i.e. α-sulfoxide)

Following the procedure of Example 2(f) but substituting [5R-[5α,6α,7β]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate in place of [6R-[6α,7β(Z)]]-3-[(acetyloxy) (methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt then [5R-[5α,6α,7β]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt (i.e. α-sulfoxide) is formed.

EXAMPLE 5i [5S-[5α,6β,7α]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt (i.e. β-sulfoxide) (a) [5S-[5α,6β,7α]]-3-[(Acetyloxy)methyl]-7-[[(amino-4 -thiazolyl)[2-methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester

Following the procedure of Example 2(d) but substituting [5S-[5α,6β,7α]]-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e. β-sulfoxide) made as in Example 4(a) for 7 ACA-diphenylmethyl ester, then [5S-[5α,6β,7α]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester is formed.

(b) [5S-[5α,6β,7α]]-3-[(Acetyloxy)methyl]-7:[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxio-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate

Following the procedure of Example 2(e) but substituting [5S-[5α,6β,7α]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 5-oxide, diphenylmethyl ester in place of [6R-[6α,7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester then [5S-[5α,6β,7α]]-3-[(acetyloxy)methyl]-7-[[(2-amino4-thiazolyl)[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate is formed.

(c) [5S-[5α,6β, 7α]]-3-[[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt (i.e. β-sulfoxide)

Following the procedure of Example 2(f) but substituting [5S-[5α,6β,7α]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate in place of [6R-[6α,7β(Z)]]-3-[(acetyloxy) (methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt then [5S-[5α,6β,7α]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt (i.e. β-sulfoxide) is formed.

EXAMPLES 6-31

Following the procedure of Examples 1 to 5 and 5i but employing the ester shown in Col. I and the acid shown in Col. II one obtains the ester shown in Col. III. Removal of the ester protecting group yields the acid product shown in Col. IV ##STR44##

    __________________________________________________________________________     Example                                                                             R.sub.4      R           R.sub.1                                                                            R.sub.2                                                                            R.sub.3 m  n                             __________________________________________________________________________                        ##STR45##  H   H   H       one                                                                               two                           7                                                                                    ##STR46##   C(CH.sub.3).sub.3                                                                          H   H                                                                                   ##STR47##                                                                             zero                                                                              one                           8                                                                                    ##STR48##                                                                                   ##STR49##  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                               zero                                                                              one                           9                                                                                    ##STR50##                                                                                   ##STR51##  H   H   CH.sub.3                                                                               zero                                                                              one                           10                                                                                   ##STR52##                                                                                   ##STR53##  H   H   CH.sub.3                                                                               two                                                                               one                           11                                                                                   ##STR54##                                                                                   ##STR55##  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                               zero                                                                              one                           12                                                                                   ##STR56##                                                                                   ##STR57##  H   H   CH.sub.3                                                                               zero                                                                              one                           13   H                                                                                            ##STR58##  H   H   CH.sub.3                                                                               zero                                                                              one                           14                                                                                   ##STR59##                                                                                   ##STR60##  CH.sub.3                                                                           H   CH.sub.3                                                                               zero                                                                              one                           15                                                                                   ##STR61##                                                                                   ##STR62##                                                                                          ##STR63##                                                                             zero                                                                              zero                          16                                                                                   ##STR64##                                                                                   ##STR65##          CH.sub.3                                                                               zero                                                                              zero                          17                                                                                   ##STR66##                                                                                   ##STR67##  H   H   CH.sub.3                                                                               one                                                                               one                           18                                                                                   ##STR68##                                                                                   ##STR69##  H   H   CH.sub.2CH.sub.3                                                                       two                                                                               one                           19                                                                                   ##STR70##                                                                                   ##STR71##  CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                               zero                                                                              one                           20                                                                                   ##STR72##                                                                                   ##STR73##  H   H   CH.sub.3                                                                               one                                                                               one                           21                                                                                   ##STR74##                                                                                   ##STR75##  CH.sub.3                                                                           H                                                                                   ##STR76##                                                                             zero                                                                              one                           22                                                                                   ##STR77##                                                                                   ##STR78##  H   H   CH.sub.3                                                                               zero                                                                              one                           23                                                                                   ##STR79##                                                                                   ##STR80##  H   H   CH.sub.3                                                                               two                                                                               one                           24                                                                                   ##STR81##                                                                                   ##STR82##  H   H                                                                                   ##STR83##                                                                             zero                                                                              one                           25                                                                                   ##STR84##                                                                                   ##STR85##  H   H                                                                                   ##STR86##                                                                             one                                                                               one                           26                                                                                   ##STR87##                                                                                   ##STR88##  CH.sub.3                                                                           CH.sub.3                                                                           H       zero                                                                              one                           27                                                                                   ##STR89##                                                                                   ##STR90##  CH.sub.3                                                                           CH.sub.3                                                                           H       zero                                                                              two                           28                                                                                   ##STR91##                                                                                   ##STR92##  H   H   H       zero                                                                              one                           29                                                                                   ##STR93##                                                                                   ##STR94##  H   H   CH.sub.3                                                                               zero                                                                              one                           30                                                                                   ##STR95##                                                                                   ##STR96##  H   H   CH.sub.3                                                                               one                                                                               one                           31                                                                                   ##STR97##                                                                                   ##STR98##  H   H   CH.sub.3                                                                               zero                                                                              one                           __________________________________________________________________________

The acid products of Examples 6 to 31 can be converted to the sodium or potassium according to known procedures.

The products of Examples 6 to 31 are obtained as the syn or anti isomer depending upon the configuration of the acid shown in Col. II. Also, when R₁ and R₂ are not the same, the products are obtained in the D-, L- or D,L-form depending upon the optical activity of the acid shown in Col. II.

EXAMPLE 32 [6R-[6α,7β(Z)]]-3-[[4-(Aminocarbonyl)pyridino]methyl]-7-[[(2-amino-4-thiazolyl)[[2-oxo-2-[(phenylmethoxy)-amino]ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (syn isomer)

A mixture of 0.005 mole of the sodium salt product of Example 1, 0.0075 mole of 4-pyridinecarboximide, 12 g of potassium thiocyanate, and 7.5 ml of water are heated at 50° for 24 hours. The resulting solution is passed through a chromatography column filled with the ion exchange Amberlite XAD-2. The column is washed with water and the titled compound is eluted with a mixture of water:methanol (8:2). The methanol is evaporated from the eluate and the aqueous solution is lyophilized. The amorphous residue is triturated with ether and filtered under suction to yield [6R-[6α, 7β(Z)]]-3-[[4-(aminocarbonyl)pyridino]methyl]-7-[[(2-amino-4-thiazolyl)[[2-oxo-2-[(phenylmethoxy)-amino]ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

EXAMPLES 33-40

Following the procedure of Example 32 by employing the cephalosporanic acid sodium salt shown in Col. I and the pyridine compound shown in Col. II, one obtains the product shown in Col. III. ##STR99##

    ______________________________________                                         Ex-                                                                            am-                                                                            ple  R.sub.1 R.sub.2 R.sub.3   m    n    R.sub.8                               ______________________________________                                         33                   CH.sub.3  one  zero                                       34                                                                                                   ##STR100##                                                                              two  zero                                                                                 ##STR101##                           35   H       H       CH.sub.3  zero one  H                                     36                   CH.sub.3  zero zero H                                     37                   CH.sub.3  one  zero                                                                                 ##STR102##                           38   CH.sub.3                                                                               CH.sub.3                                                                               CH.sub.3  zero one                                                                                  ##STR103##                           39                                                                                                   ##STR104##                                                                              zero zero H                                     40   H       H       H         zero one                                                                                  ##STR105##                           ______________________________________                                    

The products of Examples 33 to 40 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I. Similarly, when m is one the compounds are obtained as the α- or β-sulfoxide depending upon the orientation of the 3-acetoxymethyl sulfoxide starting material. Also, when R₁ and R₂ are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.

EXAMPLE 41 [6R-[6α,7β(Z)]]-7-[[(2-Amino-4-thiazolyl)[[2-oxo-2-[(phenylmethoxy)-amino]ethoxy]imino]acetyl]amino]-3-[[5-methyl-1,3,4-thiadiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt

0.002 mole of the sodium salt product of Example 1 is brought into solution in 100 ml of a phosphate buffer at a pH of 6.4. Then 0.0024 mole of 5-methyl-1,3,4-thiadiazolyl-2-thiol is added. The solution is heated at 60° for six hours. After cooling, the pH is adjusted to 7.0 and the solution is chromatographed on the ion exchange resin Amberlite XAD-2. The fraction containing the desired product is freeze dried to yield [6R-[6α, 7β-(Z)]]-7-[[(2-amino-4-thiazolyl[[2-oxo-2-[(phenylmethoxy)amino]ethoxy]imino]acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt.

Following the procedure of Example 41 but employing the cephalosporanic acid sodium salt shown in Col. I and the thiol shown in Col. II, one obtains the product shown in Col. III. ##STR106##

    ______________________________________                                         Ex.  R.sub.1 R.sub.2 R.sub.3                                                                              m    n    hetero                                    ______________________________________                                         42                   H     zero zero                                           43   CH.sub.3                                                                               CH.sub.3                                                                               CH.sub.3                                                                             two  one                                                                                  ##STR107##                               44                   CH.sub.3                                                                             one  zero                                                                                 ##STR108##                               45   H       H       H     zero one                                                                                  ##STR109##                               46                   H     one  zero                                                                                 ##STR110##                               47   H       H       H     two  one                                                                                  ##STR111##                               ______________________________________                                    

The products of Examples 42 to 47 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I. Similarly, when m is one the compounds are obtained as the α- or β- sulfoxide depending upon the orientation of the 3-acetoxymethyl sulfoxide starting material. Also, when R₁ and R₂ are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.

EXAMPLE 48 [5S[5α, 6β, 7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide sodium salt (β-sulfoxide, syn isomer)

The product of Example 5i can also be prepared by the following procedure.

1.69 g of [6R-[6α, 7β(Z)]]-3-[(Acetyloxy)methyl]7-[[(2-amino-4-thiazolyl)[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid obtained as in Example 2(e) is dissolved in 35 ml of methylene chloride and cooled to 0° C. 17 ml trifluoroacetic acid is added while stirring. 0.459 g of m-chloroperbenzoic acid is added and stirring is continued for 2.5 hours. The solvent is removed in vacuo and about 400 ml of ether is added. The precipitate is filtered off and washed with ether to yield 1.5 g of [5S[5α, 6β, 7α(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl[[2-(methoxy amino)-2-oxoethoxy]imino]acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trifluoroacetate salt having a melting point of 160° to 165° C.

This acid can be converted to its sodium salt by the procedure in Example 1(f).

EXAMPLES 49-57

Following the procedure of Example 48 the sulfides shown in Col. I can be oxidized to the β-sulfoxide shown in Col. II. ##STR112##

    ______________________________________                                         Example                                                                               R.sub.1  R.sub.2  n    R.sub.3                                                                              R.sub.4                                    ______________________________________                                         49     H        H        one  H                                                50     H        H        one  CH.sub.3                                                                              ##STR113##                                51                       zero H                                                                                     ##STR114##                                52     CH.sub.3 CH.sub.3 one  H                                                                                     ##STR115##                                53     H        H        one  H                                                                                     ##STR116##                                54     H        H        one  H                                                                                     ##STR117##                                55     H        H        one  H                                                                                     ##STR118##                                56     H        CH.sub.3 one  H                                                                                     ##STR119##                                57     CH.sub.3 CH.sub.3 one  H                                                                                     ##STR120##                                ______________________________________                                    

The products of Examples 49 to 57 are obtained in the syn or anti configuration depending upon the configuration of the sulfide starting material shown in Col. I. Also, when R₁ and R₂ are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.

The acid products of Examples 1 to 57 can also be converted to various ester forms (i.e., R is ##STR121## etc.) according to known procedures. 

What is claimed is:
 1. A compound of the formula ##STR122## wherein R is hydrogen, alkali metal, ##STR123## R₁ is hydrogen or methyl; R₂ is hydrogen or methyl;R₃ is hydrogen, lower alkyl or lower alkylphenyl; R₄ is hydrogen, --OCONH₂, ##STR124## R₇ is hydrogen or lower alkyl; R₈ is hydrogen or --CONH₂ ; R₉ is hydrogen, lower alkyl, ##STR125## R₁₀ is hydrogen or lower alkyl; R₁₁ is hydrogen, sodium or potassium; n is 1, 2, 3 or 4; m is 0, 1 or 2; p is 1, 2, 3 or
 4. 2. The compound of claim 1 wherein the ##STR126## group is in the syn configuration; n is one or twom is zero or one provided that when m is one the sulfoxide is in the β-configuration; R is hydrogen, sodium, potassium, ##STR127## or --CH₂ O--CO--lower alkyl; R₁ and R₂ are independently selected from hydrogen and methyl; R₃ is hydrogen, lower alkyl or lower alkylphenyl; R₄ is ##STR128## R₈ is hydrogen or ##STR129## R₉ is hydrogen, methyl, --(CH₂)_(p) --N(CH₃)₂, ##STR130## R₁₁ is hydrogen, sodium or potassium and p is 1 or
 2. 3. The compound of claim 2 wherein R₄ is ##STR131##
 4. The compound of claim 3, [6R-[6α, 7β(Z)]]-3-[acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)]2-oxo-2-[(phenylmethoxy)-amino]ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
 5. The compound of claim 3, [6R-[6α, 7β(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[2-oxo-2-[(phenylmethoxy)-amino]ethoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt.
 6. The compound of claim 2 wherein R₄ is ##STR132## and R₉ is hydrogen or methyl.
 7. An antibacterial pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of one or more antibacterially active compounds of the formula ##STR133## wherein R is hydrogen, alkali metal, ##STR134## R₁ is hydrogen or methyl; R₂ is hydrogen or methyl;R₃ is hydrogen, lower alkyl or lower alkylphenyl; R₄ is hydrogen, --OCONH₂, ##STR135## R₇ is hydrogen or lower alkyl; R₈ is hydrogen or --CONH₂ ; R₉ is hydrogen, lower alkyl, ##STR136## or --(CH₂)_(p) --N--(lower alkyl)₂ ; R₁₀ is hydrogen or lower alkyl; R₁₁ is hydrogen, sodium or potassium; n is 1, 2, 3 or 4; m is 0, 1 or 2; p is 1, 2, 3 or
 4. 8. The method of treating antibacterial infections in a mammalian specie which comprises internally administering an effective amount of the composition of claim
 7. 